tbuckley/cabot-search huggingface dataset:
Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion
Authors: Xiaobo Wang, Rouzanna Istvanffy, Linhan Ye, Steffen Teller, Melanie Laschinger, Kalliope N. Diakopoulos, Kıvanç Görgülü, Qiaolin Li, Lei Ren, Carsten Jäger, Katja Steiger, Alexander Muckenhuber, Baiba Vilne, Kaan Çifcibaşı, Carmen Mota Reyes, Ümmügülsüm Yurteri, Maximilian Kießler, Ibrahim Halil Gürçınar, Maya Sugden, Saliha Elif Yıldızhan, Osman Uğur Sezerman, Sümeyye Çilingir, Güldal Süyen, Maximilian Reichert, Roland M. Schmid, Stefanie Bärthel, Rupert Oellinger, Achim Krüger, Roland Rad, Dieter Saur, Hana Algül, Helmut Friess, Marina Lesina, Güralp Onur Ceyhan, Ihsan Ekin Demir
Journal: Journal of Clinical Investigation (2023)

Solid cancers like pancreatic cancer (PDAC) frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modelled in genetically-engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC comprising 295 different genotypes. This phenotype screen uncovered two GEMM of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming-growth-factor-alpha (TGFa) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGFa upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI, and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGFa-expression constituted strong prognostic factors. Therefore, TGFa-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.
Extracranial-Intracranial Bypass Surgery for Stroke Prevention
Authors: Seemant Chaturvedi, J. Marc Simard
Journal: JAMA (2023)

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PRS-ing Forward to Identify Genetic Risk in Idiopathic Pulmonary Fibrosis
Authors: Timothy S. Blackwell, Gunnar Gudmundsson
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

bulk transcriptomic data.Although the authors undertook a stringent approach to replicating their results, it is notable that even for the set of 475 persistently altered smoking genes that achieved significance across each study time point, only 41% (n = 195) of these genes were also significant in both independent replication cohorts.This level of replication is not surprising for transcriptomic data, which captures many complex signals but can be susceptible to confounding in both cross-sectional and longitudinal study designs.Although multiple stages of replication in this study provide confidence in the 195 fully replicated smoking-associated genes, further studies will be necessary to tease out adaptive versus maladaptive responses to cigarette smoke as well as the lingering consequences of smoke exposure on human health.
Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor–Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial
Authors: Soo Yeon Baek, Woo Chul Noh, Sei-Hyun Ahn, Hyun-Ah Kim, Jai Min Ryu, Seung Il Kim, Eun-Gyeong Lee, Seock-Ah Im, Yongsik Jung, Min Ho Park, Kyong Hwa Park, Su Hwan Kang, Joon Jeong, Eunhwa Park, Sung Yong Kim, Min Hyuk Lee, Lee Su Kim, Woosung Lim, Seonok Kim, Hee Jeong Kim
Journal: Journal of Clinical Oncology (2023)

To determine the updated long-term outcomes of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial.This study is a post-trial follow-up of the ASTRRA trial, involving 1,483 premenopausal women younger than 45 years treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy for estrogen receptor-positive breast cancer. Patients were randomly assigned in a 1:1 ratio to complete 5 years of tamoxifen (TAM) alone (TAM-only) or 5 years of TAM with ovarian function suppression (OFS) for 2 years (TAM + OFS). The primary end point was disease-free survival (DFS), and the secondary end point was overall survival (OS).At 106.4 months of median follow-up, there was a continuous significant reduction in the DFS event rate in the TAM + OFS group. The 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (hazard ratio [HR], 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between the two groups. The OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25).Adding OFS for 2 years to adjuvant TAM with a longer follow-up resulted in consistent DFS benefits, suggesting that adding OFS to TAM should be considered for patients who remain in a premenopausal state or resume ovarian function after chemotherapy.
P728: EVALUATION OF IPSS-M IN PATIENTS WITH MYELODYSPLASTIC SYNDROME AND SPLICEOSOME MUTATIONS
Authors: Samuel Urrutia, Ziyi LI, Emmanuel Almanza, Alex Bataller, Rashmi Kanagal-Shamanna, Jayastu Senapati, Koji Sasaki, Kelly Chien, Guillermo Montalban-Bravo, Courtney Dinardo, Gautam Borthakur, Carlos Bueso Ramos, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: HemaSphere (2023)

Background: The International Prognostic Scoring System (IPSS) has wide clinical adoption in myelodysplastic syndromes (MDS). Recently, the IPSS-Molecular (IPSS-M) was developed to handle mutations which have shown to impact prognosis in this disease. Mutations encoding for components of the spliceosome (SM) are seen in over fifty percent of patients with MDS and are mostly enriched in low-risk groups. Aims: This study seeks to validate the IPSS-M model in a cohort of 427 patients with MDS and spliceosome mutations. Methods: We calculated IPSS-M and reviewed clinical characteristics, molecular constitution, and survival outcomes of 427 patients diagnosed with MDS using the WHO 2022 criteria at a single institution from 2017 to 2022. Results: We identified 427 patients with at least one SM. SF3B1 (33%), SRSF2 (27%), U2AF1 (23%), and ZRSR2 (9%). Eight percent had more than one SM. Patients were mostly male (71%) and were classified as MDS-SF3B1 (31%), MDS-LB (30%), MDS-IB2 (17%), MDS-IB1 (17%), MDS-LB-RS (6%), MDS-f (1%) and MDS-5q (1%). Most common mutational partners were TET2 (58%), ASXL1 (38%), RUNX1 (22%), and EZH2 (20%). By IPSS-R, median overall survival (mOS) was not reached (NR) for Very Low category (HR 0.06, 95%CI 0.02-0.17), it was 4.5 years for Low (HR 0.22, 95%CI 0.13-0.37), 2.1 years for Intermediate (HR 0.43, 95%CI 0.25-0.74), 1.8 years for High (HR 0.6, 95%CI 0.34-1.03) and 1.3 years for Very High (HR reference) (c-index: 0.67). (Figure 1A) By IPSS-M mOS was NR for the Very Low category (HR 0.05, 95%CI 0.01-0.36), it was 5.8 years for Low (HR 0.14, 95%CI 0.07-0.29), 3.6 years for Moderate Low (HR 0.33, 0.17-0.61), 3.1 years for Moderate High (HR 0.4, 0.22-0.73), 1.9 years for High (HR 0.85, 95%CI 0.53-1.34) and 1.7 years for Very High (HR reference) (c-index: 0.68). A relationship between both scores is presented in Figure 1C. Patients categorized as Very Low, Low, or Moderate Low did not progress to acute myeloid leukemia. (Figure 1B) Summary/Conclusion: In patients with MDS and spliceosome mutations, IPSS-M has a similar prognostic performance compared to IPSS-R. Despite significant reclassification, the availability of the individual mutational landscape refines this score allowing it to reclassify IPSS-R risk categories without losing its prognostic power. Furthermore, no patients classified in the three lowest IPSS-M risk categories transformed to AML—a valuable clinical tool.Figure 1. A) Overall survival for IPSS-M model in 427 patients with spliceosome mutations. B) Time to AML transformation by IPSS-M. C) Re-classification schema of IPSS-R as classified by IPSS-M. Keywords: International prognostic index, Genomics, Myelodysplastic syndrome
Favorable outcomes of NPM1mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance
Authors: I. Khan, A. Kaempf, S. Raghuwanshi, M. Chesnokov, X. Zhang, Z. Wang, A. Domling, J. W. Tyner, C. Camacho, A. L. Gartel
Journal: Blood Cancer Journal (2023)

Favorable outcomes of NPM1 mut AML patients are due to transcriptional inactivation of FOXM1, presenting a new target to overcome chemoresistance
Multiple LDLR class A repeats on very‐low‐density lipoprotein receptor promote the cross‐species transmission of Semliki Forest virus
Authors: Ruolan Hu, Maochen Li, Huahao Fan
Journal: MedComm (2023)

Multiple LDLR class A (LA) repeats around LA3 promote synergistic binding to Semliki Forest virus (SFV) E1-DIII near the 2-fold and 5-fold symmetry axes. Meanwhile, the multiple consecutive LAs concatemer shows approximately 1000 times higher binding affinity than that of LA3s, which can help to effectively and synergistically bind with E1-DIII of viral envelope protein.
Hyperactivity of platelets and increased megakaryopoiesis in COVID-19 patients with acute respiratory distress syndrome
Authors: Lingna Wang, Huicong Liu, Jiaqing Liu, Haitao Yuan, Chen Wu, Xiyang Li, Kaikai Xu, Jiang Hong, Guoyan Wu, Fangfang Zhu
Journal: Med-X (2023)

Abstract The Severe Acute Respiratory Syndrome (SARS)-CoV-2-induced Coronavirus Disease 2019 (COVID-19) pandemic has caused an overwhelming influence on public health because of its high morbidity and mortality. Critical-illness cases often manifest as acute respiratory distress syndrome (ARDS). Previous evidence has suggested platelets and thrombotic events as key mediators of SARS-CoV-2-associated ARDS. However, how the balance of platelet regeneration from the hematopoietic system is changed in ARDS remains elusive. Here, we reported a more severe inflammation condition and hyperactivity of platelets in COVID-19 ARDS patients compared with those infected but without ARDS. Analysis of peripheral blood revealed an increased proportion of hematopoietic stem cells (HSCs), common myeloid progenitors (CMPs), megakaryocyte-erythrocyte progenitors (MEPs), and megakaryocyte progenitors (MkPs) in ARDS patients, suggesting a megakaryocytic-differentiation tendency. Finally, we found altered gene expression pattern in HSCs in COVID-19 ARDS patients. Surprisingly, genes representing platelet-primed HSCs were downregulated, indicating these cells are being stimulated to differentiate. Taken together, our findings shed light on the response of the hematopoietic system to replenish platelets that were excessively consumed in COVID-19 ARDS, providing a mechanism for disease progression and further therapeutic development. Graphical Abstract
P715: TOX REGULATED CD8+ T LYMPHOCYTES EXHAUSTED IN MYELODYSPLASTIC SYNDROMES PATIENTS THROUGH ACTIVATING AKT/PI3K/MTOR PATHWAY
Authors: Haiyue Niu, Mengying Zhang, Mengyuan Liu, Zonghong Shao, Limin Xing, Huaquan Wang
Journal: HemaSphere (2023)

Background: CD8+ T lymphocytes of myelodysplastic syndromes (MDS) patients are frequently exhausted, which plays a key role in the pathogenesis of MDS. Thymocyte selection-related high mobility box protein (TOX) programs CD8+ T lymphocyte exhaustion. However, the role of TOX in the CD8+ T lymphocytes of MDS patients is not clear. Aims: The aim of this study is to investigate the role of TOX in the CD8+ T lymphocytes of MDS patients. Methods: The expression of TOX, inhibitory receptors (PD-1, TIGIT, TIM3, LAG3, and CTLA4), and functional molecules (Perforin and Granzyme B) in peripheral blood T lymphocytes of MDS patients and normal controls was detected by flow cytometry. Lentiviral transduction for stable TOX-knockdown CD8+ T lymphocytes and small interfering RNA (siRNA) for TOX-knockdown Jurkat was used to investigate the relevant mechanisms. Results: The expression of TOX was enriched in CD3+CD8+ lymphocytes of MDS patients and increased gradually with the increase of risk degree (31.82% ± 12.20% in controls, 52.22% ± 15.61% in LR-MDS, 55.32% ± 19.56% in HR-MDS) (A). Moreover, the upregulation of TOX was associated with the upregulation of inhibitory receptors (PD-1, TIGIT, TIM3, LAG3, and CTLA4) and the downregulation of functional molecules such as perforin (42.27% ± 15.24% in controls, 42.50% ± 10.03% in LR-MDS, 31.20% ± 12.93% in HR-MDS) and granzyme B (35.27% ± 11.49% in controls, 32.45% ± 13.91% in LR-MDS, 27.99% ± 11.78% in HR-MDS) (B). These findings suggest that TOX plays a crucial role in the dysfunction of CD8+ T lymphocytes in MDS patients. To further investigate the role of TOX in CD8+ T lymphocytes, we knocked down TOX expression using lentiviral transduction and small interfering RNA (siRNA). We found that targeting TOX partially reversed the exhausted phenotype of CD8+ T lymphocytes and enhanced the lethality of SKM-1 cell lines (C). In addition, we found that knocking down the expression of TOX with siRNA in Jurkat cell lines improved cell proliferation activity, downregulated inhibitory receptors, and activated the AKT/PI3K/mTOR signaling pathway (D). Finally, we found that the upregulation of TOX was associated with shorter survival in MDS patients (23.9 months VS 34.5 months, HR = 3.989, P = 0.047), suggesting that TOX could be a potential prognostic biomarker for MDS. Summary/Conclusion: CD8+ T lymphocytes of myelodysplastic syndromes (MDS) patients are frequently exhausted, which plays a key role in the pathogenesis of MDS. Thymocyte selection-related high mobility box protein (TOX) programs CD8+ T lymphocyte exhaustion. However, the role of TOX in the CD8+ T lymphocytes of MDS patients is not clear.Keywords: Akt, Myelodysplastic syndrome, CD8 T cells
P714: DISSECTING THE CLINICAL HETEROGENEITY OF ISOLATED TRISOMY 8 MYELODYSPLASTIC SYNDROMES THROUGH MUTATIONAL PROFILE
Authors: Sofía María Toribio Castelló, Sandra Castaño, Angela Villaverde-Ramiro, Esperanza Such, Montserrat Arnan, Francesc Solé, Marina Díaz Beyá, María Díez-Campelo, Mónica del Rey, Teresa González, Jesus Hernández Rivas
Journal: HemaSphere (2023)

Background: Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated to clinical heterogeneity and intermediate cytogenetic risk when found isolated. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Aims: To evaluate the prognostic impact of mutational profile in patients with MDS and +8 as the only cytogenetic alteration. Methods: Targeted-deep sequencing was performed in a cohort of 108 control MDS patients and 79 cases showing isolated +8. Cytogenetics were confirmed by karyotype and FISH. Sequencing libraries were prepared according to manufacturer’s instructions (Agilent Technologies) and run out in NextSeq (Illumina). Statistical analyses were performed with SPSS and R. Results: The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p<0.0001) and shorter overall survival (23.7 vs 46.3 months, p=0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8isolated (HR: 3.1; p<0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M respectively, were re-stratified as high risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n=2 494). Summary/Conclusion: The presence of mutations in STAG2, SRSF2 and RUNX1 enable the distinction of a high risk subgroup of MDS with isolated +8. Thus, the mutational profile in isolated +8 MDS patients could offer new insights for the correct management of these patients. Keywords: Myelodysplastic syndrome, Prognostic factor, Somatic mutation, Cytogenetic abnormalities
P938: SURVIVAL OF PATIENTS WITH MULTIPLE MYELOMA IN THE GENERAL POPULATION BASED ON DATA FROM TWO FRENCH CANCER REGISTRIES
Authors: Cyrille Hulin, Sébastien Orazio, Alain Monnereau, Sophie Gauthier, Marc Maynadie, Gaëlle Desamericq, Hakima Mechiche
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: The treatment of Multiple Myeloma (MM) has changed dramatically over the past two decades with the introduction of new drugs, including immunomodulators (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib) and anti-CD38 monoclonal antibodies (daratumumab). Aims: This study aimed to estimate the survival of patients with a first diagnosis of MM. Methods: This retrospective observational cohort study was carried out in the general population using data from 2 hematological malignancies registers (Gironde, Côte-d’Or) and included all new adult patients diagnosed with MM between 2008 and 2015. Patients were followed from diagnosis until death/end of study in December 2020, allowing a follow-up period of at least 5 years for each patient included. Time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Net survival defined as the observed survival if cancer was the only possible cause of death, was also estimated. Results: The analysis was carried out on 1166 patients included. The median age was 74 years (Q1-Q3; 63-82 years) with a slightly unfavorable M/F gender ratio of 1.1. In this cohort, 923 patients (79%) had initiated treatment. Bortezomib, thalidomide and/or lenalidomide were used in first line of therapy in most cases (n=825/923, 89% of patients in 2015 vs 80% in 2008). Overall, the median follow-up time was 4.9 years, 52% of patients had died, and 1% (n=11) was lost in follow-up. Median OS for treated patients was 4.9 years (95% confidence interval [CI]:4.6, 5.3). Median OS was worse in the subgroup of patients who didn’t have a stem cell transplantation (SCT) versus those who did (3.6 vs 9.8 years), and in elderly patients (≥80 years) compared with patients <65 (2.1 vs 9.8 years). The estimated 5-year net survival was 55% for the entire cohort of treated patients and was higher among patients treated more recently (58% in 2015 vs 45% in 2008). Median PFS was 2.3 years (95% CI: 2.1, 2.4) for the entire cohort of treated patients. Median TTNT from first line to second line of therapy was 1.9 years (95% CI; 1.7, 2.1) and decreased in older patients: it was 2.6 years (95% CI: 2.3, 2.9) in patients <65 years, 2.1 years (95% CI; 1.7, 2.3) in those aged between 65 and 79, and 1.1 years (95% CI: 0.9, 1.3) in patients aged ≥80. Summary/Conclusion: These results provide important information on the efficacy of MM treatments available in France during the study period. Consistent with the 2021 published INCa data showing the 5-year net survival improved between 1995 and 2015, particularly in the youngest patients, and is expected to continue to improve in the coming years. Keywords: Treatment, Multiple myeloma, Real world data
P743: CLINICAL OUTCOMES OF PATIENTS WITH MYELODYSPLASTIC SYNDROME AND SPLICEOSOME MUTATIONS
Authors: Samuel Urrutia, Emmanuel Almanza, Alex Bataller, Koji Sasaki, Kelly Chien, Rashmi Kanagal-Shamanna, Guillermo Montalban-Bravo, Carlos Bueso-Ramos, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: HemaSphere (2023)
P759: LANDSCAPE OF BONE MARROW T CELLS IN ACQUIRED APLASTIC ANAEMIA REVEALS AN ACTIVATED STATE AND A POTENTIAL CLONAL EXPANSION
Authors: Yan Liu, Xinyi Zuo, Jun Peng
Journal: HemaSphere (2023)

Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: Acquired aplastic anaemia (AA) is a typical example of human bone marrow (BM) failure syndromes and is characterized by peripheral blood cytopenia and empty bone marrow. Previous studies have identified AA as an autoimmune disease mediated by T-cells, which attack and destroy the hematopoietic stem cells in BM. Aims: Our study aims to investigate the cellular heterogeneity, lineage and functional states of T cells that play a role in the development of AA, with the goal of shedding light on the underlying mechanisms of the disease. Methods: CD3+CD4+ and CD3+CD8+ mature T cells, isolated from BM of five newly diagnosed severe AA (SAA) patients and four healthy controls (HC) by fluorescence-activated cell sorter (FACS), were subjected to single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequences using 10X Genomics Chromium Single Cell 5’ and Single-Cell V(D)J protocols. Libraries were sequenced on Illumina NovaSeq platforms. Results: Following a rigorous quality control process, 78,391 (SAA, n = 41,253; HC, n = 37,138) single-cell profiles were included in the downstream analyses. Bioinformatic analysis of the transcriptional profiles and TCR sequences revealed their molecular and functional properties and developmental trajectory. And a total of 14 stable clusters emerged, consisting of 7 clusters for CD8+ and 7 clusters for CD4+ cells (Figure 1A). We found that CD8+ cytotoxic T lymphocytes (CTLs) in SAA exhibited stronger cytotoxicity and invasiveness compared to those in HC, and this abnormality may be involved in the destruction of bone marrow hematopoietic system in SAA. We observed an up-regulation of multiple chemokine genes and chemokine receptor genes, as well as an enhancement of IFN-α and IFN-γ response pathways in CTLs of SAA (Figure 1B). These findings suggested that CTLs in SAA exhibited an activated state. We next assessed the TCR repertoire and clonal expansion. Sequencing and analysis of the TCR repertoire can yield valuable insights into adaptive immune responses, with significant implications for the investigation of autoimmune diseases. Although the majority of cells contained unique TCRs, we observed differing levels of repeat patterns in different samples, particularly in SAA patients. The relative abundance analysis of TCR clones in all samples showed that the proportion of medium and above medium size clones was higher in SAA patients (Figure 1C). The data supported the potential clonal expansion in SAA. Summary/Conclusion: Our study provides a comprehensive reference map of human BM T cells in SAA patients. The unique characteristics of T cells observed in SAA patients suggest their potential critical role in the pathogenesis of this autoimmune disease.Keywords: Aplastic anemia, TCR, T cell